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Obstructive Sleep Apnea and Oxygen Therapy: A Systematic Review of the Literature and Meta-Analysis

1Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Stony Brook University Medical Center, Stony Brook, NY; 3Division of Pulmonary Critical Care and Sleep Medicine, University of Kentucky College of Medicine, Lexington, KY

ABSTRACT

Background:

Hypoxemia is an immediate consequence of obstructive sleep apnea. Oxygen (O2) administration has been used as an alternative treatment in patients with obstructive sleep apnea (OSA) who do not adhere to continuous positive airway pressure (CPAP) in order to reduce the deleterious effects of intermittent hypoxemia during sleep. This systematic review aims to investigate the effects of O2 therapy on patients with OSA.

Results:

We identified 14 studies including a total of 359 patients. Nine studies were of single cohort design, while 5 studies were randomized control trials with 3 groups (CPAP, oxygen, and placebo/sham CPAP). When CPAP was compared to O2 therapy, all but one showed a significant improvement in AHI. Ten studies demonstrated that O2 therapy improved oxygen saturation vs. placebo. However, the average duration of apnea and hypopnea episodes were longer in patients receiving O2 therapy than those receiving placebo.

Conclusion:

This review shows that O2 therapy significantly improves oxygen saturation in patients with OSA. However, it may also increase the duration of apnea-hypopnea events.

Citation:

Obstructive sleep apnea (OSA) is the periodic reduction (hypopnea) or cessation (apnea) of airflow due to narrowing of the upper airway during sleep, often accompanied by hypoxemia and sleep disturbance.1 The prevalence of OSA is estimated to be between 2% and 25% in the general population. OSA is linked to hypertension, ischemic heart disease, stroke, premature death, and motor vehicle crash.2–7

Oxygen desaturation is an immediate consequence of obstructive sleep apnea. Intermittent hypoxemia increases sympathetic activity and norepinephrine levels and leads to hypertension.8,9 It has also been associated with an increased risk of diabetes.10 Indeed, most of the sequelae of obstructive sleep apnea are more strongly linked to the degree and duration of oxygen desaturation than to the numbers of apneas and hypopneas or disruptions in sleep architecture.11 The resolution of nocturnal intermittent hypoxemia associated with sleep apnea is a major goal of the treatment of patients with obstructive sleep apnea.

Many treatment approaches have been employed for the treatment of moderate to severe OSA, but CPAP is the treatment of choice and has been widely prescribed.12,13 In placebo-controlled and uncontrolled studies, CPAP has been shown to reduce apnea-hypopnea index (AHI) and to improve hypoxemia associated with respiratory events during sleep.14,15 CPAP adherence has been reported to be as low as 50%, at least in part because it is a burdensome treatment.16

Oxygen administration has been used as an alternative treatment in patients with OSA who are not somnolent or not compliant with CPAP; the purpose of supplemental oxygen in this situation is to reduce the deleterious effects of transient hypoxemia during sleep.17 Supplemental oxygen has been shown to be effective in improving the AHI, respiratory arousal index, and nocturnal desaturation during apneic episodes.18 However, oxygen therapy may lengthen apnea duration, thus accelerating CO2 retention.19

This systematic review aims to investigate the effects of CPAP and oxygen on patients with OSA. This review addresses the following questions: (1) Does evidence from controlled trials support the preferential use of CPAP over oxygen for improving OSA symptoms? (2) Can oxygen therapy be safely used in patients who are non-adherent with CPAP?

METHODS

For purposes of this analysis, the target population consisted of adult humans with a diagnosis of obstructive sleep apnea defined as an AHI > 5 events per hour. The diagnosis of OSA was made using polysomnography (PSG). The study intervention included either the CPAP and oxygen therapy or oxygen therapy compared with the placebo. Outcomes of interest included the effects on AHI, nocturnal hypoxemia, apnea duration, and arousal index.

Literature Search

The literature search was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and meta-analysis) guidelines.20 The databases Medline, Embase, Cochrane Central Register of Controlled Trials (1st Quarter 2011), Cochrane Database of Systematic Reviews (from 1950 to Feb 2011) were thoroughly searched to include all available evidence for the systematic review. We developed and executed the search strategy with the help of an expert librarian familiar with the literature search protocol of the Cochrane Collaboration. The following target population keywords were used for the literature search: “obstructive sleep apnea,” “obstructive sleep apnea syndrome,” “obstructive sleep apnea-hypopnea syndrome,” “sleep disordered breathing,” “obesity hypoventilation syndrome” and “apnea-hypopnea,” “sleep apnea syndrome and “apnea.” The target intervention keywords used were “oxygen”, “oxygen therapy,” “oxygen inhalational therapy,” “CPAP,” “positive airway pressure,” and “continuous positive airway pressure.” The results of the target population were combined with the target intervention results (using an “and”). Studies focusing on central sleep apnea were excluded by including “NOT central sleep apnea” in the search strategy. The search strategy was limited to English language abstracts and adult human population. Duplicate records, if any were removed from the final search result. We also reviewed the reference lists of relevant articles to retrieve potentially relevant articles.

Medline (Ovid SP) (1948 to Feb 2011)

EMBASE (1980 to Feb 2011)

Cochrane Database of Systematic Reviews (1st quarter 2011)

Cochrane Central Controlled Trials Registry (1st quarter 2011)

The databases of the Cochrane Library were used to confirm the completeness of the search. The time period searched was 1948 to 2011.

Study Selection

The search results were evaluated by two independent reviewers (VM, TSV). First, irrelevant papers were excluded by reviewing the title of the records. Next, the abstract and/or full text articles of the remaining papers were retrieved and carefully evaluated to determine if they met the eligibility criteria.

All prospective studies, including randomized and non-randomized placebo controlled trials were included if they reported the effects of CPAP treatment or oxygen therapy on AHI, oxygen saturation, apnea duration, and arousal index in patients with OSA. Studies not reporting at least one of these outcomes were excluded. All observational studies were graded for strength of evidence according to the Oxford level of evidence.21 We used the Cochrane risk of bias tool to assess the risk of bias for 6 randomized controlled trials (Table 1).22

Cochrane risk of bias in included studies

Table 1

Data Extraction

Data extraction was completed by two reviewers (VM, TSV) and validated by the senior author (FC). Various data extracted from these studies included the type of study, level of evidence, number of patients receiving the study intervention, type of study intervention, duration and effects of intervention on AHI, SpO2, arousal index, and apnea duration. We divided the studies into 2 groups: the first group included studies which used CPAP and O2 treatment; the second group included studies which used only O2 therapy as an intervention. The methodological qualities of the included studies were independently evaluated by the first author (VM), if any doubt the senior author was consulted (FC). Individual authors were contacted via emails for the details of the results

Statistical Analysis

We performed the meta-analyses by using fixed-effects model if no heterogeneity was present. In order to assess the heterogeneity between studies, we used χ2 tests and estimated the I2 statistic. We considered the heterogeneity to be present if the p value on the χ2 test was < 0.05. In the presence of heterogeneity, we pooled the results by using random-effects (DarSemonian and Laird method) model. The standardized mean difference was used to pool continuous variables that used different scales. We performed separate random-effects meta-analyses among randomized controlled studies comparing CPAP, placebo CPAP, and oxygen. We did not correct for multiple comparisons.

RESULTS

The Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines were followed for the description of the search strategy. Our search strategy yielded 4,793 citations (Figure 1). In the first session of screening, most studies were eliminated based on the predetermined eligibility criteria, leaving 105 articles. In the second session, 105 articles were evaluated and 14 articles were identified as meeting the inclusion criteria, with subsequent exclusion of 91 articles. Articles were excluded for the following reasons: Non-pertinent papers—excluded by abstract/full-text review (n = 64), O2 therapy in pediatric OSA (n = 11), reviews papers (n = 10), correspondence (n = 4), and case reports (n = 2).

Flowchart of the literature search indicating number of papers in each condition

Figure 1

Flowchart of the literature search indicating number of papers in each condition

Study Characteristics

Tables 2 and 3 summarize study characteristics included in the systematic review. There were 6 studies23–28 that used a randomized control design with 3 groups, each group being assigned to CPAP, placebo CPAP, or O2 to evaluate the effects of CPAP and O2 on AHI, O2 saturation, and arousal indices. Eight studies29–36 used a single cohort in which the outcome was measured in the same study population before and after the study intervention. All of these observational studies compared the effects of room air with O2 on mean oxyhemoglobin saturation, sleep disordered breathing (SDB) events, and SDB event duration. These 8 studies were graded according to Oxford level of evidence and had a 2b level of evidence. We could not pool the results from the study by Block et al.33 because the authors did not provide the standard deviation for the outcome of interests.

Table 3

Patient Characteristics

Table 2 represents a group of patients who received CPAP and O2 intervention versus placebo CPAP. Table 3 represents a group of patients who received O2 intervention compared with control (air). A total of 359 patients were included in the 14 studies. All the patients had a diagnosis of OSA confirmed by in-laboratory polysomnography. The inclusion criteria of the patients differed among the studies selected for the review. Two studies23,33 used AHI > 5; 5 studies24–28 used AHI > 15; one study32 used SDB event > 50/h, and one study35 used RDI > 20 for OSA patient selection. Four studies30,31,34,36 selected patients with a confirmed diagnosis of OSA following overnight PSG with no description of any specific AHI criteria. Most of the patients were male, accounting for 89% of the study population. All the patients in the reported studies had moderate to severe OSA with AHI ranging from 20.5 ± 5 to 88.2 ± 27. The duration of the study intervention across the different studies was in the range of 1 night to 3 months.

Effects on Oxygenation, Respiratory Events, and Sleepiness

Table 2 summarizes the effects of the different treatment modalities on AHI, SpO2 and arousal events studied by 6 RCTs. The respiratory disturbances occurring during the nighttime in OSA patients were measured using AHI, respiratory disturbance index (RDI), or SDB events. When CPAP was compared with O2, CPAP was significantly more effective in reducing AHI, while O2 was shown to be more effective in elevating the mean SpO2 and mean nadir SpO2 during hypoxemic events. Both CPAP and O2 improved the oxygenation as compared to placebo (sham) CPAP; this effect was statistically significant (p < 0.05). Four studies showed that CPAP versus O2 therapy was more effective in improving the arousal events/total arousal index, but we could not pool the arousal events for the meta-analysis because of insufficient data.

The effects of CPAP and oxygen supplementation on the daytime somnolence was evaluated by 2 studies.23,24 In one study, nasal CPAP was more effective in improving objectively measured daytime sleepiness than oxygen. This effect was apparent due to the significant efficacy of CPAP in lengthening the multiple sleep latency test (MSLT) time compared to baseline.23 Similarly, another study showed the effectiveness of CPAP in reducing Ep-worth Sleepiness Scale score; however, it was not statistically different from placebo-CPAP or supplemental oxygen.24

Effects on Systemic Blood Pressure

Three studies showed the treatment outcome on systemic blood pressure in patients treated with CPAP, oxygen, and placebo-CPAP.23,25,26 Two studies showed that CPAP effectively reduced both the systolic as well as the diastolic blood pressure as compared to oxygen (p < 0.05).25,26 In one study, CPAP and oxygen both had the effects in lowering the systolic blood pressure as compared to diastolic blood pressure; however, the changes were not statistically significant.23

The effects of O2 therapy on the oxygen saturation and SDB events are summarized in Table 3. Seven studies showed that oxygen therapy was effective in improving the oxygenation as compared to air (control) in OSA patients. The SDB events showed a decreasing trend in the number of events when the patients received O2 therapy after breathing room air. One study demonstrated an improved cardiovascular status in OSA patients following oxygen enrichment night.34 Similarly, another study showed an improvement in daytime somnolence in patients receiving oxygen therapy.35

Meta-Analysis of Randomized Controlled Trials

Effect of CPAP versus oxygen on apnea hypopnea index (AHI)

Figure 2

A pooled analysis of 5 randomized controlled trials demonstrated that the use of therapeutic CPAP lead to a statistically significant reduction in the AHI versus nocturnal administration of oxygen (SMD -3.37, 95% CI -4.79 to -1.96). There was also a statistically significant reduction in AHI in CPAP group versus placebo (SMD -3.65, 95% CI -5.31 to -1.98). Nocturnal oxygen did not show significant reduction in AHI compared to placebo CPAP (SMD -0.32, 95% CI -0.74 to 0.08).

Figure 3

A pooled analysis of 4 studies that reported mean oxyhemoglobin saturation showed that both therapeutic CPAP and nocturnal administration of oxygen lead to significant improvement in oxyhemoglobin saturation compared to placebo CPAP. Comparison of CPAP to nocturnal oxygen did not demonstrate a significant difference in the degree of improvement in oxygenation (SMD 0.07, 95% CI -0.27 to 0.41).

Effects on Sleep Disordered Breathing (SDB) Event Duration

We identified 5 observational studies reporting the SDB event duration as an outcome.30–33 We could not pool the results of these studies for statistical analysis due to the lack of sufficient data. However, 3 of these studies reported that administration of oxygen lead to the prolongation of SDB event duration.31–33

DISCUSSION

In this systematic review, we identified and reviewed 14 studies evaluating the effects of oxygen supplementation for the treatment of intermittent nocturnal hypoxemia in patients with OSA. We performed a meta-analysis of the six randomized controlled trials that evaluated the effect of CPAP, placebo CPAP, versus oxygen on AHI and SpO2. In this analysis, patients with obstructive sleep apnea who used CPAP had signifi-cant reduction in AHI compared to those who used nocturnal oxygen. However, both nocturnal oxygen and CPAP improved oxyhemoglobin saturation equally.

Obstructive sleep apnea is a prevalent disorder with its serious health related consequences.37 Many patients with sleep apnea have intermittent episodes of hypoxemia at night secondary to the periods of the upper airway obstruction. These episodes have been shown to be associated with harmful sequelae including insulin resistance, cognitive deficit, and the development of other cardiovascular morbidity.38–40 Both nasal CPAP and nocturnal administration of oxygen improve oxy-hemoglobin saturation, but nocturnal oxygen has little effect on the blood pressure surge following apneas in patients with sleep apnea.41–43 On the other hand, CPAP has been shown to lower the blood pressure variability in patients with sleep apnea.25,26 This suggests that there might be some other factors such as hypercapnia, arousals, respiratory efforts, intrathoracic pressure changes, or fragmented sleep contributing to the increase in the blood pressure seen in sleep apnea.44–47 In a study in human adults, the arousals from NREM sleep was shown to increase the sympathetic discharge with increase in the systolic blood pressure.48

Patients with OSA frequently have cognitive dysfunction and excessive daytime sleepiness (EDS), possible secondary to the combination of hypoxemia and fragmented sleep. These symptoms worsen with increasing severity of hypoxemia and increasing frequency of arousals. Nasal CPAP improves both the arousals and hypoxemia and thereby has been shown to improve the sleepiness in contrast to the nocturnal administration of oxygen.23,49–51 On the other hand, both CPAP and oxygen supplementation have been shown to improve psychological symptoms, including depression.27

CPAP is clearly the treatment of choice in patients with OSA due to its immediate efficacy. It has been shown to improve AHI, hypoxemia, and arousals, thereby improving sleepiness and hypertension in contrast to the nocturnal administration of oxygen. However, patient adherence to CPAP is less than optimum.52 In one study, adherence to CPAP was reported to be higher in patients who had consultation with the sleep physician prior to undergoing the sleep study,53 but adherence to CPAP is between 50% and 70%, even with excellent management.54

Hypoxemia is a major problem for patients with OSA in the postoperative period and hypoxemic episodes have been reported to occur mostly between the postoperative nights two to five.55 Up to 40% of patients undergoing abdominal or thoracic surgery may experience postoperative hypoxemia.56 In particular, surgical patients with OSA are at high risk of having postoperative complications.57,58 A recent cohort study showed that oxygen desaturation with SpO2 < 90% was the most common postoperative complication in patients with OSA.59 These hypoxemic episodes have been shown to have serious consequences, including poor wound healing, cardiac arrhythmias, and delirium.60,61 The use of supplemental oxygen in the perioperative period has been shown to reduce nausea and vomiting and hospital length of stay, and to improve wound healing.62–64

Long-term oxygen therapy (LTOT) has been shown to improve survival and quality of life in patients with COPD.65–67 However, its role in obstructive sleep apnea treatment is more controversial. The administration of nocturnal oxygen leads to the improvement of intermittent hypoxemia in patients with OSA. It may be considered in hypoxemic patients with OSA who are intolerant to the other treatment modalities for sleep apnea. However, the long-term consequences of chronic nocturnal administration of oxygen are unknown in patients with OSA. Further nocturnal oxygen has been shown to prolong apnea duration in patients with OSA, perhaps as a result of the suppression of the hypoxic respiratory drive.31–33 In an observational study, the rise in blood pressure following each apneic episode was primarily linked to apnea duration and was not linked to hypoxemia.42 Prolonged apnea duration may also increase the severity of hypercarbia and acidosis in patients with OSA.19,31,32 This potential risk mandates careful monitoring for arrhythmias and other consequences of hypercarbia, especially in those with comorbid lung disease.

In conclusion, the evidence from the controlled trials does support the preferential use of CPAP over oxygen in patients with OSA since CPAP significantly improves the oxyhemoglobin saturation and reduces AHI and systemic blood pressure with improvement in daytime sleepiness. On the other hand, oxygen therapy is a double-edged sword, which not only lengthens the apnea duration but potentially increases the risk of hypercarbia with minimal to no effect on blood pressure and daytime sleepiness. Hence, at present it is difficult to recommend oxygen therapy for patients who are non-adherent with CPAP until the results of a multicenter clinical trial, Heart Biomarker Evaluation in Apnea Treatment, are available.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

ACKNOWLEDGMENTS

The authors would like to thank Marina Englesakis, BA (Hons), MLIS, Information Specialist, Health Sciences Library, University Health Network, Toronto, Ontario, Canada for her assistance with the literature search.